ES2338698T3 - PROCESS TO PREPARE ACID 3ALFA (BETA) -7ALFA (BETA) -DIHIDROXI-6ALFA (BETA) -ALQUIL-5BETA-COLANICO. - Google Patents

Abstract

Process for preparing 3α-7α(β)-dihydroxy-6α(β)-alkyl-5β-cholanic acid (I) in which R is a linear or branched C1-C5 alkyl and the relative intermediates 3α-hydroxy-6β-alkyl-7-keto-5β-cholanic (VIII) and 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX).

Description

Acid preparation process 3? (?) -7? (?) -Dihydroxy-6? (?) -Alkyl-5? -Collanic.

Scope of the present invention

The present invention relates to a process to prepare acids 3? -7? (?) -Dihydroxy-6? (?) -Alkyl-5? -Collanics.

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Technical status

Farnesoid X receptors (FXR) are, in principle, orphan nuclear receptors, first identified  once from a rat liver cDNA library (B.M Forman and others, Cell. 81: 687-693 (1995)), and belong to the family of nuclear receptors of factors of transcription activated by ligands, including the receptors of steroid, retinoid and thyroid hormones (D.J. Mangelsdorf and others, Cell. 83: 841-850 (1995)).

Various bile acids of natural type, and in particular chenodeoxycholic, deoxycholic, lithocolic and the respective conjugates with taurine and glycine, fix and activate FXRs in physiological concentrations, as described in WO00 / 37077.

It is also believed that FXRs intervene in the regulation of bile acid and homeostasis cholesterol.

WO 02/072598 describes acids 3-?, 7-? -Dihydroxy-6? -Alkyl- (allyl) -5? -Collanics  of general formula (A)

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one

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where R 'is ethyl, propyl or allyl, which are also farnesoid receptor agonists X.

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Specifically, the compound of the formula (I) in which R '= ethyl is two or more times potent than acid Chenodeoxycholic, the most potent FXR natural agonist.

The compounds of the formula (I) - used especially to increase HDL cholesterol and decrease triglycerides for disease prevention and treatment Hepatic of cholestatic origin - they are prepared by a process which comprises the following stages:

i)

acid reaction 3-? -Hydroxy-7-keto-5? -Collanic of formula (II)

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2

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quad

with dihydropyran, to obtain the respective acid 3-? -Tetrahydropyranyloxy-7-keto-5? -Collanic  of formula (B)

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3

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ii)

reaction of compound (B) with an alkyl bromide of formula R'Br in which R 'has the meanings indicated above, to obtain the compound (C)

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4

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iii)

reduction of compound (C) with sodium borohydride to give (D)

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5

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iv)

hydrolysis of (D) to give the compounds (TO).

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Although this process consists of few stages, It presents a series of drawbacks.

First, at all stages, the reaction products are purified on a chromatographic column, that is, a very expensive method of separation that cannot be carried out at industrial scale

In addition the reaction performance in the stage (ii) is extremely low (12-13%), with a considerable decline in overall performance, which is less than 3.5%

Also at this stage, it is used as a reagent hexamethylene phosphonamide, which is an agent known carcinogen.

Summary of the present invention

The applicant has now found a process which allows to obtain the compounds of the general formula (I)

6

where the link represented by a dashed line at position 6 and 7 indicates that the substituent it can go in position α or β, chosen from the class formed by:

i)

acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of the general formula (AI)

7

ii)

acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of the general formula (IB)

8

iii)

acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of the general formula (IC)

9

where R is an alkyl C1-C5 linear or branched, and comprising following stages

to)

esterify acid 3α-hydroxy-7-keto-5β-cholanic (II)

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10

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quad

in methanol and in an acidic medium, to obtain 3α-hydroxy-7-keto-5β-cholanate of methyl (III),

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eleven

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b)

whistle 3α-hydroxy-7-keto-5β-cholanate of methyl (III) with trimethylchlorosilane to obtain the correspondent 3-? -Trimethylsiloxy-7-keto-5? -Colanate (IV),

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12

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C)

whistle the 3-? -Trimethylsiloxy-7-keto-5? -Colanate of methyl (IV) obtained in step (b) with trimethylchloro-silane in the presence of a strong base to get 3α-, 7α-di-trimethylsiloxy-6-en-5β-colanate  methyl (V),

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13

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d)

make react 3α-, 7α-di-trimethylsiloxy-6-en-5β-colanate of methyl (V) with the aldehyde R-CHO, in which R has the meanings indicated above, and with a Lewis acid, to get 3α-hydroxy-6-alkylidene-7-keto-5β-colanate  methyl (VI),

14

and)

hydrolyze the 3α-hydroxy-6-alkylidene-7-keto-5β-colanate from methyl to acid 3α-hydroxy-6-alkylidene-7-keto-5β-collanic  (VII),

fifteen

F)

hydrogenate the acid 3α-hydroxy-6-alkylidene-7-keto-5β-collanic in an alkaline medium with Pd / C to acid 3α-hydroxy-6β-alkyl-7-keto-5β-collanic

16

g)

optional intermediate heat treatment (VIII) in an alkaline medium to obtain the corresponding acid 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX)

17

h)

reduce the ketone group in position (7) of intermediate (VIII) or (IX) to 7-hydroxyl group, according to one of the following alternative conditions of operation:

h ')

reduce the acidic compound 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX) with metal hydride to 3α- acid, 7α-di-hydroxy-6α-alkyl-5β-cholanic  (IA),

h '')

reduce the acidic compound 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX) in the presence of sodium and alcohol, to obtain acid 3α-, 7β-di-hydroxy-6α-alkyl-5β-cholanic (IC),

h '' ')

reduce acid 3α-hydroxy-6β-alkyl-7-keto-5β-collanic (VIII) in the presence of a metal to acid hydride 3α-, 7α-di-hydroxy-6β-alkyl-5β-cholanic (IB).

The process according to the present invention has considerable advantages over the processes known above described, especially for obtaining acids 3α-, 7α-di-hydroxy-6α-alkyl-5β-collagens  (IA). Indeed, although it consists of many stages, it allows to obtain the product of formula (I) with overall returns clearly satisfactory (24.6%), in any case far superior to those of known process In addition it is not necessary to purify the intermediates and the use of very toxic reagents such as hexamethylene phosphonamide.

Finally, with the process of the present invention, as indicated above, new ones can be obtained compounds of formula (IB), in which R is an alkyl C 1 -C 5 linear or branched, and (IC), in which R is a linear C2-C5 alkyl or branched, which can be used as hepatoprotectors, especially for the treatment and prevention of liver diseases of origin cholestatic

Therefore the present invention relates to pharmaceutical compositions containing, as active ingredient, at least one of the acids (I-B) and (I-C) and the respective pharmaceutically salts acceptable, in combination with excipients and / or diluents adequate.

Detailed description of the present invention

The acid esterification reaction 3-hydroxy-7-keto-5β-cholanic (II) in step (a) of the process of the present invention, preferably performed at a temperature between 30 and 60 ° C in a acidic medium, preferably methanesulfonic acid.

The silylation reaction of the hydroxyl group in 3? position of 3α-hydroxy-7-keto-5β-cholanate  of methyl contemplated in step (b) of the process of the present invention is preferably carried out in a non-polar solvent, with more preferably an aromatic solvent, especially toluene, in presence of a hydrogen ion acceptor consisting of an amine tertiary aliphatic, alicyclic or heteroaromatic type, of preference triethylamine.

According to a form of execution especially preferred the 3α-trimethylsiloxy-7-keto-5β-colanate  of methyl is not isolated or purified before using it in the stage (c), but at this stage the oily residue obtained is used after evaporating the reaction solvent, of which they have previously removed the salts by extraction with water.

The following silylation of the ketone group in position 7 contemplated in step (c) of the present process invention is preferably carried out using as a strong base a alkaline amide obtained from ammonia or an alkaline amide of an aliphatic secondary amine. In a solution particularly Preference is given to using lithium diisopropylamide as a strong base. This reaction is preferably carried out in a solvent. aprotic polar and said solvent is more preferably tetrahydrofuran.

According to a preferred embodiment the product obtained in step (c) is not isolated or purified before of using it in the next stage (d), but in this stage the oily residue obtained after evaporating the reaction solvent, from which the salts by extraction with water.

Step (d) is preferably performed in a apolar solvent, preferably chosen from the halides of I rent; more preferably this solvent is chloride of methylene

Step (d) is preferably performed using boron trifluoride etherate as Lewis acid, at a temperature between -90 and 60ºC, for a period of 2 to 4 hours, in presence of the aldehyde R-CHO, in which R has the Desired meanings.

Then the mixture is reacted to a temperature between 0 and 35 ° C for a period of 1 to 6 hours.

In this case the product obtained in the stage (d) it is neither isolated nor purified before using it in the next step (e), but the oily residue obtained is used after evaporating the reaction solvent, of which they have previously removed by extraction with water the salts and water soluble components.

Step (e) is preferably carried out in an alcoholic solvent, preferably methanol, in the presence of an alkali hydroxide, which is more preferably a solution 30% aqueous sodium hydroxide.

The temperature is preferably comprised between 20 and 60ºC.

The product of the reaction stage (e) is isolated preferably after acidifying, crystallizing it with a organic solvent preferably chosen from ethyl and acetone, possibly in the presence of water.

The hydrogenation reaction contemplated in the step (f) is preferably carried out in an aqueous medium, in presence of an aqueous solution of sodium hydroxide, with a pressure between 1 and 3 atmospheres. When the present process invention contemplates the realization of step (g) and if specifically the compounds of general formula (IA) or (IC) must be prepared, this stage is preferably carried out directly in the reactive mixture from hydrogenation and takes place, preferably, by heating said reaction at a temperature between 95 and 105 ° C for a few hours to allow epimerization of the 6-? -ethyl group a 6-? -Ethyl.

The reaction product from the stage (f) or the possible step (g) is isolated from the reaction mixture preferably using the following conditions of operation:

one)

the aqueous solution of which it has been acidified catalyst removed by filtration, preferably with acid 85% phosphoric,

2)

ethyl acetate is added to the mixture obtained in the stage (1) and everything is heated to a temperature between 40 and 70 ° C,

3)

then it is cooled to a temperature between 0 and 30 ° C and the resulting precipitate is filtered and then dry

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When the reduction of stage (h) is carried out according to the operating conditions contemplated in step (h '), to obtain the compound of formula (IA), or according to the conditions operations contemplated in stage (h '' '), to obtain the compound of formula (IB), of the process of the present invention, the metal hydride is preferably sodium borohydride and the reduction reaction is carried out in an aqueous solution alkaline The reaction preferably takes place at a temperature. between 70 and 105 ° C for 1 hour.

Instead, when the stage reduction (h) it is carried out according to the operating conditions contemplated in the step (h ''), which preferably takes place in an alcohol C 1 -C 5 linear or branched, with greater preference in sec-butyl alcohol, at the temperature of solvent reflux. The product obtained in step (h ') or (h '' ') is preferably isolated under the following conditions operational:

one')

add an immiscible solvent to the reaction mixture with water, preferably a non-polar solvent such as methylene, and acidify the mixture, preferably with acid phosphoric,

2')

stir and let the resulting mixture stand, eliminating the aqueous phase,

3')

extract the product from the organic phase with water and ammonia,

4')

add phosphoric acid to the resulting aqueous phase and stir everything for a few hours at a temperature between 20 and 50 ° C,

5')

recover and dry the precipitated product by filtration.

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The process of the present invention is particularly suitable for preparing compounds of formula (I) in that R is preferably methyl.

For illustrative, but not limiting, purposes they provide some examples of preparation of the compounds of the formula (I) and specifically of (IA), (IB) and (IC), in which R = methyl, according to the process of the present invention.

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Example 1 Acid preparation process 3α-, 7α-dihydroxy-6α-ethyl-5 β-cholanic of formula (IA) in which R = methyl a) Preparation of 3α-hydroxy-7-keto-5β-cholanate methyl (III)

17.0 kg of acid are loaded into a reactor 3? -Hydroxy-7-keto-5? -Collanic, 68 kg of methanol and 0.17 kg of acid methanesulfonic acid Then the reaction mixture is heat at 30-60 ° C for 1 hour and 25.5 are added kg of demineralized water. Then the resulting mixture is stirred and cool to 20-25 ° C, until you get a good precipitation, then continue to cool until 0-15 ° C. The precipitate is filtered and washed with a mixture of water and methanol, and then dried in an oven at about 40 ° C. Thus 15 kg of 3α-hydroxy-7-keto-5β-cholanate  of methyl (III). Stoichiometric yield: 85.2%.

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b) Preparation of 3-? -Trimethylsiloxy-7-keto-5? -Colanate methyl (IV)

15.0 kg of 3α-hydroxy-7-keto-5β-cholanate of methyl, 45 kg of toluene, 7.5 kg of triethylamine and 7.5 kg of trimethylchlorosilane.

The mixture is heated at 70-80 ° C and kept stirring at this temperature for approximately 1 hour, then 37.5 kg of water and the mixture are added Stir at 15-20 ° C. It is then separated and removed. the lower phase, aqueous. The organic phase is concentrated until obtain an oily residue, to which 15 kg of tetrahydrofuran.

The resulting solution, which contains 3-? -Trimethylsiloxy-7-keto-5? -Colanate of methyl (IV) is used in the following step (c).

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c) Preparation of 3α-, 7α-di-trimethylsiloxy-6-en-5β-colanate methyl (V)

In a reactor 30 kg of tetrahydrofuran, is brought to a temperature between -90º and -60ºC, it add 9.8 kg of lithium diisopropylamide and 9.3 kg of trimethylchlorosilane and pour the entire solution of tetrahydrofuran prepared in (b) containing 3-? -Trimethylsiloxy-7-keto-5? -Colanate of methyl The mixture is then stirred at a temperature between -60º and -90 ° C for about 1 hour. Then a solution is poured  4.5 kg of sodium bicarbonate and 60 kg of water and the mixture is stir at 0-10 ° C, the lower aqueous phase is separated and eliminates Then the organic phase is concentrated until a oily residue, to which 45.0 kg of chloride are added methylene

The solution of 3α-, 7α-di-trimethylsiloxy-6-en-5β-colanate of methyl thus obtained is sent to the next step (d).

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d) Preparation of 3α-hydroxy-6-ethyliden-7-keto-5β-colanate of methyl (VI) in which R = methyl

In a reactor the entire solution of 3α, 7α-di-trimethylsiloxy-5β-colanate of methyl in methylene chloride from the previous example and it is cooled to -90 / -60 ° C. Then 1.97 kg of acetaldehyde are added and 5.5 kg of boron trifluoride etherate. The reaction mixture is keep stirring at said temperature for 2/4 hours. It is then heated to 30-35 ° C and maintained at that temperature for about 2/4 hours. Then 60 are added kg of water The obtained mixture is stirred and the aqueous phase is separated. The resulting solution that contains 3α-hydroxy-6-ethyliden-7-keto-5β-colanate of methyl is sent to the next stage.

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e) Acid preparation 3α-hydroxy-6-ethyliden-7-keto-5β-cholanic (VII) in which R = CH 3

The solution of 3α-hydroxy-6-ethyliden-7-keto-5β-colanate of methyl in methylene chloride obtained in the previous step. The solvent is then removed by distillation, until a oily residue to which 15 kg of methanol are added.

Then the reaction mixture is heated to 45-50º C, 7.5 kg of sodium hydroxide are poured into 30%, and kept at the previous temperature for 1 hour approximately. Then 30 kg of water are added and then 45.0 kg of methylene chloride and 7.5 kg of 85% phosphoric acid. The lower organic phase is separated and then the phase is removed watery The solvent is removed from the organic phase by distillation, until a pasty residue is obtained. Are added approximately 37.5 kg of ethyl acetate to the residue, the mixture is heat to 65-75 ° C and then cool to 10-35 ° C. The resulting precipitate, filtered and washed with ethyl acetate, dried. 8.0 kg of acid are obtained 3α-hydroxy-6-ethyliden-7-keto-5β-cholanic with a stoichiometric yield of 51.8% calculated with respect to 3α-hydroxy-7-keto-5β-cholanate of methyl

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f) Acid preparation 3? -Hydroxy-6? -Ethyl-7-keto-5? -Collanic (IX) in which R = CH 3

8.0 kg of acid are loaded into a reactor 3α-hydroxy-6α-ethyliden-7-keto-5β-collanic, 48.0 kg of water, 5.1 kg of 30% sodium hydroxide, 0.80 kg of 5% palladium / carbon. The reaction mixture is hydrogenated at a pressure between 1 and 3 atmospheres, until absorption of hydrogen.

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g) Preparation of acid 3? -Hydroxy-6? -Ethyl-7-keto-5? -Collanic (IX)

At the end of the reaction the mixture is heated to 95-105 ° C and is maintained at this temperature for some hours to allow the acid 3? -Hydroxy-6? -Ethyl-7-keto-5? -Collanic (VIII) become the corresponding acid epimer 3? -Hydroxy-6? -Ethyl-7-keto-5? -Collanic (IX) desired.

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The suspension is filtered and the catalyst. 5.1 kg of 85% phosphoric acid and 9.6 kg of ethyl acetate to the filtered solution and the reaction mixture is heats at a temperature between 40 and 70 ° C. It cools to a temperature between 0 and 30 ° C and the precipitate is recovered by filtration. After washing with ethyl acetate the precipitate is Dry in an oven at 65 ° C. 5.0 kg of acid are obtained 3α-hydroxy-6α-ethyl-7-keto-? -Collanic.  Stoichiometric yield: 62.2%.

18

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Analysis Acid 3? -Hydroxy-6? -Ethyl-7-keto-5? -Collanic (IX)

C_ {26} H_ {42} O_ {p} p.f. 185-188 ° C

NMR-H1 analysis made with the Bruker device DRX-ADVANCE-400 hz, dissolving the Sample on CD_3 OD, gave the following results:

0.62 ppm (s, 3 H of C18 methyl); 0.76 ppm, J = 7.4 Hz (t, 3 H of C26 methyl); 0.89 ppm J = 6.5 Hz, (d, 3 H , C 21 methyl); 1.18 ppm (s, 3 H , C 19 methyl), 2.21 ppm (m, 2 H , -CH 2 - C 23); 2.50 ppm, J = 11.17 Hz (,, C H in C 8); 2.85 ppm J = 13 Hz and J = 5.4 Hz (dd 1 H in C 6), 3.50 ppm (m, C H in C 3).

NMR-C13 analysis made with the Bruker device DRX-ADVANCE-200 hz, dissolving the shows object of analysis in a mixture of CD_ {3} OD and CDCl3, gave the following results:

212.82 ppm (C7); 179.44 ppm (C 24), 71.26 ppm (C 3), 54.77 ppm (C 17), 51.98 ppm (C 14), 18.84 ppm (C 21), 18.34 ppm (C 26), 12.09 ppm (C_ {18}).

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h ') Acid preparation 3-?, 7? -Dihydroxy-6? -Ethyl-5? -Collanic of formula (I) in which R = methyl

5.0 kg of acid are loaded into a reactor 3α-hydroxy-6α-ethyl-7-keto-? -Collanic, 5.0 kg of water and 2.50 kg of sodium hydroxide. This mixture is then heat to 70-105 ° C and pour a mixture of sodium borohydride dissolved in 2.5 kg of water, then the mixture is Keep warm for 1 hour, cool to temperature ambient and 10.0 kg of demineralized water, 15.0 kg of methylene chloride and 3,000 kg of 85% phosphoric acid. It shakes the mixture, the lower organic phase is separated and the phase is removed watery

The crude product crystallizes by cooling the organic solution This product dissolves in 50 kg of water demineralized and 1.10 kg of 30% ammonia. Then the mixture is stir until complete dissolution and maintained at 20-50 ° C, and 1.50 kg of phosphoric acid are poured. Be Stir the precipitated mixture - always at a temperature between 20 and 50 ° C - then the precipitate is recovered by filtration, washed with Water and dry.

4.50 kg of acid are obtained 3-?, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic of formula (I), in which R = methyl. Stoichiometric performance: 89.6%

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Example 2 Acid preparation 3-? -, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic of formula (IB) in which R = methyl

Acid 3α-hydroxy-6β-alkyl-7-keto-5β-collanic of formula (VIII) prepared in the manner described in steps (a) - (f) from example 1 and isolated in the manner described in step (g) is reduced under the same operating conditions described in step (h ') from Example 1. Acid is obtained 3-?, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic  of formula (IB) in which R = methyl.

Analysis

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19

Acid 3-?, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic (IB)

C_ {26} H_ {44} O_ {p} p.f. 115-118 ° C

NMR-H1 analysis made with the Bruker device DRX-ADVANCE-400 hz, dissolving the Sample on CD_3 OD, gave the following results:

0.70 ppm (s, 3 H of C18 methyl); 0.95 ppm (s, 3 H , of C 19 methyl), 1.00 ppm, J = 7.65 Hz (t, 3 H of C 26 methyl); 1.45 ppm J = 3.5 Hz, (d, 3 H , C 21 methyl); 2.25 ppm (m, 2 H , -CH 2 - of C 23); 3.40 ppm (m, C H in C 3), 3.62 ppm (m, C H in C 7).

NMR-C13 analysis made with the Bruker device DRX-ADVANCE-200 hz, dissolving the shows object of analysis in a mixture of CD_ {3} OD and CDCl3, gave the following results:

177.91 ppm (C 24), 72.18 ppm (C 3), 71.68 ppm (C7); 55.79 ppm (C 17), 50.83 ppm (C 14), 18.17 ppm (C 21), 14 ppm (C 26), 11.60 ppm (C 18).

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Example 3 Acid preparation 3-?, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic of formula (IC) in which R = methyl

Intermediate (IX) is prepared according to the operating conditions described in steps (a) - (g) of the example 1 and added until complete dissolution sec-butyl alcohol, in which sodium has previously dissolved in molar ratios between 3: 1 and 3: 2 with respect to compound (IX). Be get acid 3-?, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic  of formula (IC) in which R = methyl.

Analysis Acid 3-?, 7? -Di-hydroxy-6? -Ethyl-5? -Collanic (IC)

C_ {26} H_ {44} O_ {p} p.f. 217-219 ° C

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twenty

NMR-H1 analysis made with the Bruker device DRX-ADVANCE-400 hz, dissolving the Sample on CD_3 OD, gave the following results:

0.56 ppm (s, 3 H of C18 methyl); 0.73 ppm, J = 7.4 Hz (t, 3 H of C26 methyl); 0.81 ppm (s, 3 H , of C 19 methyl), 0.82 ppm J = 4.60 Hz, (d, 3 H , of C 21 methyl); 2.21 ppm (m, 2 H , -CH 2 - of C 23), 3.80 ppm (br, O- H of hydroxyl in C 3, in C 7, and of carboxyl C_ {24}); 3.10 ppm (m, C H in C 7); 3.44 ppm (m, C H in C 3).

NMR-C13 analysis made with the Bruker device DRX-ADVANCE-200 hz, dissolving the shows object of analysis in a mixture of CD_ {3} OD and CDCl3, gave the following results:

179 ppm (C 24), 75, 65 ppm (C 7), 71.87 ppm (C 3), 56 ppm (C 17), 55 ppm (C 14), 18.4 ppm (C 21), 12.24 ppm (C 26), 11.20 ppm (C 18).

Claims (43)

1. Process to prepare to prepare acids 3? -7? (?) -Di-hydroxy-6? (?) -Alkyl-5? -Collanics  of general formula (I) twenty-one where the link represented by a dashed line at position 6 and 7 indicates that the substituent it can go in position α or β, chosen from the class formed by:

i)

acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of the general formula (AI)

22

ii)

acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of the general formula (IB)

2. 3

iii)

acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of the general formula (IC)

24 where R is an alkyl C 1 -C 5 linear or branched, and comprising the following stages

to)

esterify acid 3α-hydroxy-7-keto-5β-cholanic (II)

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25

quad

in methanol and in an acidic medium, to obtain 3α-hydroxy-7-keto-5β-cholanate of methyl (III),

26

b)

whistle 3α-hydroxy-7-keto-5β-cholanate of methyl (III) with trimethylchlorosilane to obtain the correspondent 3-? -Trimethylsiloxy-7-keto-5? -Colanate (IV),

27

C)

whistle the 3-? -Trimethylsiloxy-7-keto-5? -Colanate of methyl (IV) obtained in step (b) with trimethylchloro-silane in the presence of a strong base to get 3α-, 7α-di-trimethylsiloxy-6-en-5β-colanate  methyl (V),

28

d)

make react the 3α-, 7α-di-trimethylsiloxy-6-en-5β-colanate of methyl (V) with the aldehyde R-CHO, in which R has the meanings indicated above, and with a Lewis acid, to get 3α-hydroxy-6-alkylidene-7-keto-5β-colanate methyl (VI),

29

and)

hydrolyze 3α-hydroxy-6-alkylidene-7-keto-5β-colanate from methyl to acid 3α-hydroxy-6-alkylidene-7-keto-5β-collanic  (VII),

30

F)

hydrogenate the acid 3α-hydroxy-6-alkylidene-7-keto-5β-collanic in an alkaline medium with Pd / C to acid 3α-hydroxy-6β-alkyl-7-keto-5β-collanic

31

g)

optional intermediate heat treatment (VIII) in an alkaline medium to obtain the corresponding acid 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX)

32

h)

reduce the ketone group in position (7) of intermediate (VIII) or (IX) to 7-hydroxyl group, according to one of the following alternative conditions of operation:

h ')

reduce the acidic compound 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX) with metal hydride to 3α- acid, 7α-di-hydroxy-6α-alkyl-5β-cholanic (IA),

h '')

reduce the acidic compound 3α-hydroxy-6α-alkyl-7-keto-5β-cholanic (IX) in the presence of sodium and alcohol, to obtain acid 3α-, 7β-di-hydroxy-6α-alkyl-5β-cholanic (IC),

h '' ')

reduce acid 3α-hydroxy-6β-alkyl-7-keto-5β-collanic (VIII) in the presence of a metal to acid hydride 3α-, 7α-di-hydroxy-6β-alkyl-5β-cholanic (IB).

2. Process according to claim 1, characterized in that the esterification step (a) is carried out at a temperature between 30 and 60 ° C in an acid medium. 3. Process according to claim 2, characterized in that said acid is methanesulfonic acid. 4. Process according to one of claims 1-3, characterized in that the silylation step (b) is carried out in a non-polar solvent, in the presence of a hydrogen ion acceptor. 5. Process according to claim 4, characterized in that said apolar solvent is an aromatic solvent. 6. Process according to claim 5, characterized in that said aromatic solvent is toluene. 7. Process according to claim 4-6, characterized in that said hydrogen ion acceptor is a tertiary amine of the aliphatic, alicyclic or heteroaromatic type. 8. Process according to claim 7, characterized in that said tertiary amine is triethylamine. 9. Process according to one of claims 1-8, characterized in that the methyl 3-? -Trimethylsiloxy-7-keto-5? -Colanate (IV) obtained in step (b) is not isolated or purified before of using it in step (c). 10. The process according to claim 9, characterized in that the oily residue obtained after evaporating the reaction solvent is used as reagent (IV) in step (c), from which the salts have been previously removed by extraction with water. 11. Process according to any of claims 1-10, characterized in that the subsequent silylation of the ketone group in step (c) is carried out using an alkaline amide obtained from ammonia or a secondary amine as a strong base. 12. Process according to claim 11, characterized in that said alkaline amide is lithium diisopropylamide. 13. Process according to any of claims 1-12, characterized in that said step (c) is carried out in a polar aprotic solvent. 14. Process according to claim 13, characterized in that said polar aprotic solvent is tetrahydrofuran. 15. Process according to any one of claims 1-14, characterized in that the methyl 3α-, 7α-dithrimethylsiloxy-6-en-5β-colanate (V) obtained in step (c) is not isolated nor is it purified before using it in step (d). 16. Process according to claim 15, characterized in that the reagent (V) used is the oily residue obtained after evaporating the reaction solvent, from which the salts have been previously removed by extraction with water. 17. Process according to any of claims 1-16, characterized in that step (d) is carried out in an apolar solvent. 18. Process according to claim 17, characterized in that said apolar solvent is an alkyl halide. 19. Process according to one of claims 17 and 18, wherein said solvent is methylene chloride. 20. Process according to any of claims 1-19, characterized in that the Lewis acid is boron trifluoride etherate. 21. Process according to claim 20, characterized in that step (d) is carried out according to the following operating conditions: the reaction mixture is cooled to a temperature between -90 ° C and -60 ° C for a period of 2 to 4 hours and then maintained at a temperature between 0 and 35 ° C for a period of 1 to 6 hours. 22. Process according to any of claims 1-21, characterized in that the methyl 3α-hydroxy-6-alkylidene-7-keto-5β-colanate (VI) obtained in step (d) is neither isolated nor It is purified before using it in the next step (e). 23. Process according to claim 22, characterized in that the hydrolysis in step (e) is carried out using as reagent (VI) the oily residue obtained after evaporating the reaction solvent, from which the salts and water-soluble components have been previously removed by water extraction 24. Process according to any of claims 1-23, characterized in that the hydrolysis reaction in step (e) is carried out in an alcoholic solvent, in the presence of an aqueous solution of an alkaline hydroxide. 25. Process according to claim 24, characterized in that said reaction is carried out at a temperature between 20 and 60 ° C. 26. Process according to any of claims 1-25, characterized in that the hydrogenation in step (f) is carried out in an aqueous medium, in the presence of an aqueous solution of sodium hydroxide, at a pressure between 1 and 3 atmospheres. 27. Process according to any one of claims 1-26, characterized in that, when it comprises step (g), it is carried out directly in the reactive mixture resulting from step (f). 28. Process according to claim 27, characterized in that said step (g) is carried out at a temperature between 95 and 105 ° C for a few hours. 29. Process according to any of claims 1-28, characterized in that the reaction product obtained in step (f) - when the process does not include stage (g) - or stage (g) is isolated from the reaction mixture according to the following operating conditions:

one)

acidification of the aqueous solution of which it has been catalyst removed by filtration,

2)

addition of ethyl acetate to the mixture obtained in stage (1) and heating the entire mixture between 40 and 70 ° C,

3)

cooling at a temperature between 0 and 30 ° C, filtration and drying of the resulting precipitate.

30. Process according to any of claims 1-29, characterized in that, when the reduction of step (h) is carried out according to the operating conditions contemplated in step (h ') or (h''') the metal hydride is borohydride sodium in an aqueous solution in which an alkaline hydroxide has dissolved. 31. Process according to claim 30, characterized in that said alkali hydroxide is a 30% sodium hydroxide solution. 32. Process according to claim 30-31, characterized in that the reaction is carried out at a temperature between 70 and 105 ° C for 1 hour. 33. Process according to claim 30-32, characterized in that the product obtained is isolated according to the following operating conditions:

one')

addition of a water immiscible solvent to the reactive mixture and acidification of the mixture with acid phosphoric,

2')

stirring and then standing the mixture obtained, and elimination of the aqueous phase,

3')

product extraction from the organic phase with water and ammonia,

4')

addition of phosphoric acid to the aqueous phase resulting and stirring of the entire mixture at a temperature between 20 and 50 ° C,

5')

recovery of precipitated product by filtration and dried.

34. Process according to any one of claims 1-29, characterized in that, when step (h) is performed according to the operating conditions (h '') the reduction reaction is carried out in a C 1 -C 5 alcohol. linear or branched, at the reflux temperature of the solvent. 35. Process according to claim 34, characterized in that said alcohol is sec-butyl alcohol. 36. Process according to any of the claims 1-35, wherein R is preferably methyl. 37. Process according to any of the claims 1-30 for preparing acid 3-?, 7-? -Dihydroxy-6? -Ethyl-5b-collanic. 38. Acid 3-? -Hydroxy-6? -Alkyl-7-keto-5? -Collanic (VIII)

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33 where R is an alkyl Linear C1-C5 branched.

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39. Acid 3-? -Hydroxy-6-? -Alkyl-7-keto-5? -Collanic (IX)

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3. 4 where R is an alkyl Linear C1-C5 branched.

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40. Acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of general formula (IB)

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35 where R is an alkyl Linear C1-C5 branched.

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41. Acid 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanic of general formula (IC) 36 where R is an alkyl Linear C1-C5 branched.

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42. Pharmaceutical composition that bears as active ingredient at least one of the acids 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanics  according to claim 40 or the respective salts pharmaceutically acceptable, in combination with excipients and / or suitable diluents. 43. Pharmaceutical composition that bears as active ingredient at least one of the acids 3-?, 7-? -Dihydroxy-6-? -Alkyl-5? -Collanics  according to claim 41 and the respective salts pharmaceutically acceptable, in combination with excipients and / or suitable diluents.